Combining two active ingredients in one pharmaceutical unit to improve patient compliance is known in literature. It can be either in the form of two or more active ingredients in immediate release form or a combination of immediate release and modified release form. There are various techniques by which the combination of immediate release and modified release is formulated in single dosage form.
Several examples of formulations having combination of immediate release active ingredient and modified release active ingredient are described below.
Shoichi Higo and Kazuo Igusa describes in U.S. Pat. No. 5,985,843 various types of pharmaceutical formulations, which consists of a delayed release of sucralfate and an immediate release fraction of another active ingredient. The pharmaceutical dosage forms are a tablet formulation containing immediate release and delayed release granules; a two or three layer tablet; a tablet with delayed release core surrounded by immediate release shell; a delayed release tablet/granule coated with a film of immediate release active ingredient.
Similarly Jurgen Zeidler et. al describes in U.S. Pat. No. 6,001,391 a process for producing solid combination tablets, which have at least two phases. The one of the two phases is processed by melt extrusion technique and contains a water soluble or swellable binder.
A compressed V-shaped center scored double layer tablet is disclosed by George M. Krause et. al in U.S. Pat. No. 3,336,200, one layer of which contains immediate release Active Ingredient and the other layer contains sustained release Active Ingredient. The tablet is divisible in two equal halves.
Similarly Jacob A. Glassman described in U.S. Pat. No. 4,503,031 a super fast starting, slow release medicinal tablet, wherein the tablet is comprised of two layers of compressed matrix that are fused together by means of readily dissolvable adhesive substance.
Allan A. Rubin describes in U.S. Pat. No. 6,238,699 B1 a pharmaceutical dosage form of carbidopa and levodopa where both the Active Ingredients are present as immediate release and sustained release. The formulation is in the form of inlay tablet or bilayered tablet or a capsule containing pellets.
Block Jurgen et. al. describes in PCT application No. WO 01/72286 A1 a formulation of vitamin composition whereas a beadlet comprises a slow release core coated by a controlled release coating. The sustained release core is coated with an immediate release layer.
Richard Ting and Charles Hscao describes in U.S. Pat. No. 6,372,254 B1 a press coated, pulsatile active ingredient delivery system which comprises a core of immediate release, enveloped by an extended release compartment.
The need to use active ingredients with different and complementary mechanisms of action frequently arises in treatment of diabetes. There are several reasons to do this, namely, the disease itself is progressive, with deterioration of glycemic control over time; mono-therapeutic attempts to achieve and maintain glycemic control often fail in the long run; multiple defects in the disease and consequently primary drug failures (1,2,3).
Current guidelines for combination therapy advise the use of agents with differing and complementary mechanisms of action in order to maximize therapeutic activity and reduce toxicity. Earlier introduction of combination therapy is increasingly being recommended. The commonly combined active ingredients include biguanides (metformin)+sulphonylureas, biguanides+PPAR? agonists(thiazolidinediones), sulphonylureas+thiazolidinediones, non-sulfonylurea secretagogues (repaglinide)+biguanides etc. Fixed dose combinations of many of the above mentioned co-administer active ingredients have also been approved by the FDA. Most of these combinations are conventional formulations combined together into a single tablet. However, because of the disparity in the duration of action (half-life), these combinations are given twice or thrice a day.
To reduce this disparity in the duration of action, a novel strategy would be to combine a sustained release formulation of one active ingredient (shorter duration of action) with conventional formulation (long duration of action) of another active ingredient. This would make it possible to give the active ingredients in same dosing frequency.
This type of combination will give better compliance and a relative freedom from mealtime drug administration, thus, improving the quality of life. More importantly, because of prolonged duration of action, it shall produce a stricter control of blood glucose and consequently less diabetic complications.
The techniques described above do not work well when the difference in the dose of active ingredients are high for example where the weight ratio of active ingredients is from 1:1 to 1: 15000 and the dose of modified release active ingredient per unit is from 500 mg to 1500 mg. The techniques described in the prior art do not give good results when the active ingredient is highly soluble. The weight of the dosage form becomes very high, or complicated process for manufacturing is required, or accurate dosing of low dose active ingredient is difficult when the techniques reported in the prior art are utilized to make formulation with high dose, high solubility active ingredient in the form of modified release and low dose active ingredient into immediate release or modified release form where the weight ratio of low dose active ingredient and high dose, high solubility active ingredient is from 1:1 to 1:15000 and the weight of modified release active ingredient per unit is from 500 mg to 1500 mg and also it is inconvenient to swallow due to large size.
Accordingly a need exists for a dosage form providing combination of immediate release and modified release active ingredients and providing solution to problems associated with dosage forms described in prior art. Further, the dosage form should be simple and economical to produce.
Therefore an object of the present invention is a dosage form of combination of a high dose, high solubility active ingredient as modified release and a low dose active ingredient as immediate release where the weight ratio of immediate release active ingredient and modified release active ingredient is from 1:1 to 1:15000 and the weight of modified release active ingredient per unit is from 500 mg to 1500 mg.
Another object of the present invention is a dosage form, which is suitable for swallowing for humans containing two active ingredients one of which is in modified release form and other in immediate release form.
Accordingly, an object of the present invention to provide a dosage form, which uses dual retard technique to control the release of the high dose, high solubility active ingredient and significantly reduce the amount of release controlling agents which are otherwise required in very high quantity and make the dosage form very bulky and therefore pose difficulty in swallowing.
A further object of the present invention is to provide a dosage form, containing one active ingredient in an immediate release form and another active ingredient as modified release and the release or disintegration of the immediate release active ingredient is not hindered by the modified release ingredient.
Another object of the present invention is to provide a dosage form, which effectively avoids the problem of separation of layers of multilayered tablets.
A further object of the present invention is a formulation, which gives accurate dosing and is prepared by conventional and simple processes.
A further object of the present invention is to provide a dosage form, which can be given twice a day or more preferably can be given once a day.
A further object of the present invention is to provide a dosage form, wherein low dose active ingredient can optionally be also in a form of modified release.